The human immunodeficiency virus (HIV) is the cause of acquired immune deficiency syndrome (AIDS) (Barre-Sinoussi, F., et al., 1983, Science 220:868-870; Gallo, R., et al., 1984, Science 224:500-503). AIDS first appeared in a single individual in the early 1980's, and has now become a worldwide pandemic. By the end of 2002, nearly 42 million people were infected, and since the start of the epidemic, more than 22 million people have died. Thus, the current global HIV pandemic ranks among the greatest infectious disease scourges in human history.
HIV transmission readily occurs through exposure of the oral, rectal, or vaginal mucosa to the virus during sex, by inoculation with contaminated blood products, through the use of contaminated equipment during injection drug use, by maternal circulation, or by breast feeding. Sexual transmission accounts for more than 90% of the world wide infections. As a result, individuals in their most productive years of life are overrepresented in the population of infected, disabled, and dying individuals, and this gives rise to enormous economic, and social consequences.
Spread of the disease is facilitated by the long latency period of the virus. Since individuals with HIV infections can be asymptomatic for many years before they develop severe immunodeficiency (AIDS), these infected, asymptomatic individuals can unknowingly transmit the virus to many sexual partners over the years.
Unfortunately, there is still no effective vaccine to protect individuals against infection with HIV, nor is there a cure for HIV-1 infection. The virus's ability to replicate within the host immune cells and the high rate of mutation and genomic evolution combine to make vaccine development difficult, and the ability of the virus to “hide” within the nervous system where it is hard for drugs to penetrate, has so far made a cure impossible.
Complications of HIV-1 infection and acquired immunodeficiency syndrome are a primary cause of morbidity and mortality associated with HIV-1 infection, and significantly reduce the quality of life for people living with AIDS. Although the exact mechanism by which the virus causes complications is not completely understood, it is known that some complications are related to the immune deficiency, whereas others are a secondary consequence of infection with the virus itself.
It has been proposed that some of the complications of HIV-1 infection may be due to HIV-1 proteins acting on infected cells or bystander cells. Certain HIV-1 proteins, such as Tat and Vpr, may enter cells via non-receptor mechanisms to influence cell function and possibly to effect changes that lead to some of the complications that are a consequence of infection with the virus itself. HIV-1 proteins that influence the development of complications through their action on infected cells or bystander cells may derive from virions that undergo degradation or lysis, or as proteins released by infected cells. Whatever their origin, these proteins may be present within extracellular fluid or in plasma.
Immunoassays for the routine detection of HIV-1 infection are known in the art. HIV-1 disease progression can be routinely monitored by measuring the number of circulating CD4 lymphocytes and the quantity of viral RNA in the blood. Alternatively, progression can be monitored by measuring the HIV-1 Gag protein p24 in biologic samples, though this may be less accurate gauge of viral activity than measurements of viral RNA. However, to date there is no clinical assay to detect, or diagnose the complications of HIV-1 that may derive from HIV-1 proteins acting on infected cells or bystander cells.
If the hypothesis that the level of one or more of the regulatory or accessory proteins, e.g. Vpr, correlates with one or more of the complications of HIV-1 infections, then the measurement of these proteins in biologic fluids may be important in the diagnosis and management of HIV-1 complications. Early diagnosis of HIV-1 complications would permit a patient to make decisions about management of their disease that may ultimately improve their quality of life and their ability to live with the disease.
Clearly then, what is needed is a means by which complications of HIV-1 can be routinely detected, diagnosed, and monitored. The invention disclosed herein addresses these and other needs.